We plan to investigate the endocrine mechanisms involved in the control of growth and differentiation of melanoma cells in tissue culture. We are interested in delineating the biochemical pathways involved in the cAMP-mediated induction of tyrosinase in these cells. We intend to determine (1) the cellular target sites for cyclic AMP, (2) the importance of such target interactions to the hormonal response, and (3) what transcriptional and translational events are required for the endocrine-induced phenotypic (melanogenic) response. We also intend to study the effects of various hormones or other chemical messengers on melanoma growth, enzyme (adenylate cyclase, tyrosinase) activity, and differentiation (melanogenesis). In addition to MSH, the following agents, known to exert physiological effects on several cell types, will be studied: steroid hormones (estradiol, testosterone, cortisol, cortisone, corticosterone and vitamin D), thyroid (T3 and T4) hormones, pituitary growth hormone and prolactin, indoleamines (melatonin, serotonin, and related structures), parathormone, calcitonin, somatostatin, glucagon, insulin, and nerve growth factor. We hope to elucidate the cellular pathways through which these hormones exert their effects on the melanogenic process. Since numerous cell systems require calcium for regulating the cellular response to hormonal stimulation, the role of calcium ions in mediating the action of MSH, vitamin D, and other hormones, will be investigated. Calcium ionophores will be used in these studies. Finally, we intend to determine the structure-activity requirements for MSH action on melanoma cells. To accomplish this, MSH peptides and related partial structures will be prepared by organic synthesis and tested for their membrane binding affinity and ability to induce the melanogenic response.